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Biomedical subjects

R A Memon

Publications and source records attributed to R A Memon.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effects of lipoproteins on cyclo-oxygenase and lipoxygenase pathways in human platelets.

The products of arachidonic acid (AA) metabolism in platelets play an important role in platelet shape change, adhesion and aggregation which may participate in the pathogenesis of ischemic heart disease and thrombosis. Since lipoproteins are also involved in the pathogenesis of thrombo-embolic disorders, the effect of human lipoproteins (HDL, LDL, VLDL) on AA metabolism in human platelets was investigated. Lipoproteins were separated by density gradient zonal ultracentrifugation. The effects of lipoproteins on production of AA metabolites in human platelets i.e., thromboxane A2 (TXA2) and hydroxy-eicosatetraenoic acids (HETEs) were examined using radiometric thin layer chromatography coupled with automated data integrator system. In human platelets, HDL inhibited 12-HETE and TXA2 formation in a concentration-dependent manner. LDL had a strong inhibitory effect on TXA2 production and a weak inhibitory effect on 12-HETE production. VLDL had no effect on platelet AA metabolism. These findings point to a new facet of lipoproteins action and suggest that lipoproteins may have a physiological role in the regulation of AA metabolism in platelets.

Adult↗
PubMed1997

Low serum HDL-cholesterol is associated with raised tumor necrosis factor-alpha during ENL reactions.

The concentrations of serum lipids and tumor necrosis factor (TNF) were measured in leprosy patients across the spectrum of the disease and in erythema nodosum leprosum (ENL) patients at the onset of the reaction and after the reaction had clinically subsided. Lepromatous/borderline lepromatous (LL/BL) patients had significantly higher serum triglyceride and lower HDL-cholesterol levels; there was no such change in the tuberculoid/borderline tuberculoid (TT/BT) patients. The household contacts (HC) of the LL/BL patients also had significantly lower serum HDL levels. ENL patients during the acute phase of the reaction had significantly lower total, LDL-, HDL-cholesterol levels compared to the stable LL/BL patients, and these changes were reversible to pre-ENL levels after the reaction had subsided. Serum TNF levels were significantly higher in household contacts and in LL/BL patients but were not statistically different in TT/BT patients. Serum TNF levels were also significantly higher during the acute phase of ENL, and declined after the clinical remission of the reaction to levels comparable with those of LL/BL patients. There was a significant negative correlation between serum TNF and HDL-cholesterol levels during and after ENL reaction. However, there was no such correlation between TNF and total or LDL-cholesterol levels in ENL patients. Our results suggest that the changes in HDL-cholesterol metabolism are a specific part of the host response to lepromatous leprosy and to the ENL reaction and may be mediated by increased TNF production.

Adolescent↗
PubMed1997

Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic squalene synthase activity, protein, and mRNA levels in Syrian hamsters.

Recent studies have shown that endotoxin (LPS) administration to Syrian hamsters markedly increased hepatic HMG-CoA reductase activity, protein mass, and mRNA levels, but only produced a modest increase in hepatic cholesterol synthesis, suggesting that LPS may also influence other key enzymes involved in the regulation of cholesterol metabolism. In the present study, we have examined the effect of LPS and cytokines on the activity, protein mass, and mRNA level of squalene synthase, which is the first committed enzyme in cholesterol biosynthesis and is located at a branch point in the mevalonate pathway. Our results demonstrate that LPS administration produces a marked decrease in the mRNA levels of squalene synthase. This decrease in squalene synthase mRNA occurred very rapidly (90 min after LPS) and required relatively small doses of LPS (1 microg/100 gm body weight). LPS also significantly decreased squalene synthase activity and protein mass. Finally, LPS produced a marked decrease in squalene synthase mRNA, activity, and protein levels when the basal levels of squalene synthase expression were increased 4-fold by prior treatment with bile acid binding resin, colestipol. Tumor necrosis factor and interleukin-1, which mediate many of the metabolic effects of LPS, also decreased hepatic squalene synthase activity and mRNA levels. Taken together, our results suggest that the discordant regulation of HMG-CoA reductase and squalene synthase during the host response to infection and inflammation may have substantial effects on the regulation of substrate flux into the non-sterol pathways of mevalonate metabolism.

Animals↗
PubMed1996

Alterations in serum lipids in lepromatous leprosy patients with and without ENL reactions and their relationship to acute phase proteins.

The concentrations of serum lipids were measured in patients with lepromatous (LL/BL) leprosy and erythema nodosum leprosum (ENL). The relationships between serum lipid levels and serum amyloid A (SAA) and C-reactive protein (CRP) were also examined in these patients. LL/BL patients had significantly higher serum triglyceride and lower HDL-cholesterol concentrations compared to the endemic controls. ENL patients had significantly lower total, HDL- and LDL-cholesterol levels compared to the endemic controls. The levels of all lipid metabolites also were significantly lower in ENL patients compared to LL/BL patients. The concentrations of SAA and CRP were markedly elevated in ENL patients but were not statistically different in LL/BL patients compared to control subjects. There was a significant negative correlation between SAA and HDL-cholesterol levels in both stable lepromatous and reactional (ENL) patients; there was no statistically significant correlation between CRP and HDL-cholesterol levels. SAA levels also had a significant negative correlation with total and LDL-cholesterol levels. Our results indicate that serum lipids are significantly altered in patients with lepromatous disease and ENL reaction. Our results also suggest that an increase in SAA levels may divert the metabolism of lipoproteins from hepatocytes toward macrophages, resulting in a decrease in serum lipoprotein levels.

Acute-Phase Proteins↗
PubMed1995

Altered platelet activating factor metabolism in insulin dependent diabetes mellitus.

Diabetes mellitus is associated with several abnormalities of platelet function. Recent studies have shown that the blood level of platelet activating factor (PAF), a potent inducer of platelet aggregation, is elevated in insulin dependent diabetes mellitus (IDDM) and remains unchanged in non-insulin dependent diabetes mellitus (NIDDM) patients. However, the mechanism of this increase in PAF levels has not been determined. In this study we have measured the activity of plasma PAF acetylhydrolase (an enzyme that regulates PAF levels) and lipoprotein levels in control subjects and diabetic patients. The data presented show that plasma PAF acetylhydrolase activity is significantly decreased in IDDM and is not altered in NIDDM patients. The lipoprotein levels were similar in control and diabetic subjects and there was no correlation between lipoprotein levels and PAF acetylhydrolase activity. These results suggest that the elevated levels of PAF in IDDM patients could be due to a decrease in plasma PAF acetylhydrolase activity.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1995

Impaired mitochondrial protein synthesis in streptozotocin diabetic rat hepatocytes.

Diabetes is associated with decreased protein synthesis; however, there have been very few studies on the effects of insulin or diabetes on mitochondrial protein synthesis. We have recently shown that insulin has a direct stimulatory effect on mitochondrial protein synthesis in isolated rat hepatocytes. In this study we demonstrate that mitochondrial protein synthesis is severely curtailed in hepatocytes isolated from diabetic rats and is unresponsive to in vitro insulin addition. Treatment of diabetic rats with insulin for three days partially restored tracer carbon incorporation in mitochondrial proteins. These results suggest that insulin stimulates hepatic mitochondrial protein synthesis which is significantly impaired in diabetes.

Animals↗
PubMed1995

Impaired mitochondrial metabolism and reduced amphibolic Krebs cycle activity in diabetic rat hepatocytes.

Oxidation of [2,3(14)C] and [1,4(14)C] succinate carbons in the mitochondrial Krebs cycle (KC) was used as a probe to investigate the effect of insulin and diabetes on mitochondrial metabolism in isolated rat hepatocytes. The data presented show that mitochondrial oxidation of succinate carbons and their incorporation into protein and lipid was markedly lower in diabetic and insulin treated diabetic rat hepatocytes. Unlike controls, diabetic rat hepatocytes were unresponsive to in vitro insulin addition. Amphibolic channeling of [2,3(14)C] succinate carbons into amino acid fraction was reduced in hepatocytes from diabetic rats, however, more of these carbons were diverted into the gluconeogenesis pathway. These data suggest that the diminished level of anabolic activities in the diabetic rat hepatocytes may be due to impairment in the KC reactions and a subsequent reduction in amphibolic channeling of metabolic intermediates.

Animals↗
PubMed1994

Fatty acid synthesis in obese insulin resistant diabetic mice.

Diabetes is associated with hypertriglyceridemia and it has been suggested that the intestine contributes to this elevation. Recent studies have shown that in animals with IDDM, fatty acid (FA) synthesis is decreased in the liver and increased in the small intestine (SI). The purpose of the present study was to measure FA synthesis in the liver and SI of animals with NIDDM. In both db/db and ob/ob animals the incorporation of 3H2O into FA was increased in the SI (10 fold in db/db and 2.2 fold in ob/ob). FA synthesis was also increased in the liver of NIDDM (9 fold in db/db and 6 fold in ob/ob). These results provide further evidence that diabetes leads to changes in lipid metabolism in the SI.

Animals↗
PubMed1993

Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride metabolism in mice.

The host response to infection is frequently accompanied by changes in cholesterol and triglyceride (TG) metabolism. To determine the role of cytokines in mediating these changes, we studied the effects of endotoxin (LPS), tumor necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1) on cholesterol and TG metabolism in C57Bl/6 (LPS-sensitive) mice and in C3H/HeJ (LPS-resistant) mice whose macrophages do not produce TNF and IL-1 in response to LPS. Sixteen hours after administration, LPS (1 micrograms/mouse) produced a 41% increase in serum cholesterol and a 62% increase in serum TG levels in C57Bl/6 mice whereas a 100-fold higher dose of LPS did not have a significant effect in C3H/HeJ mice. LPS (1 microgram/mouse) also produced a 8.6-fold increase in hepatic cholesterol synthesis and a 2.7-fold increase in hepatic fatty acid synthesis in C57Bl/6 mice but had no effect in C3H/HeJ mice. This suggests that macrophage produced cytokines such as TNF and IL-1 may be involved in mediating these effects of LPS. Additionally, LPS also increased the activity of hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. As seen with LPS, TNF and IL-1 also increased serum cholesterol and TG levels in C57Bl/6 mice. Moreover, TNF and IL-1 produced a 2.3- and 2.1-fold increase in hepatic HMG-CoA reductase activity, respectively. Finally, pretreatment of mice with anti-TNF antibodies, but not with an IL-1 receptor antagonist, blocked the effect of LPS on serum cholesterol and TG levels, hepatic cholesterol and fatty acid synthesis, and hepatic HMG-CoA reductase activity. These results suggest that whereas both TNF and IL-1 mimic the effects of LPS on cholesterol and TG metabolism, TNF may be the in vivo mediator of these late effects of LPS in mice.

Animals↗
PubMed1992

Lack of hormonal stimulation of pyridoxine metabolism in isolated rat hepatocytes.

Isolated hepatocytes obtained from Sprague-Dawley rats (145-175 g) were incubated for 15 min at 30 degrees C in Krebs-Henseleit bicarbonate buffer, pH 7.4, containing 0.5 mM concentration of each of the 20 natural amino acids and either 4.5 or 23 microM [U-14C]pyridoxine. Pyridoxine, pyridoxal, pyridoxal phosphate, and pyridoxic acid separated by an anion-exchange chromatographic technique were quantified using a phosphate analyzer and a liquid scintillation counter. The conversion of [U-14C]pyridoxine to its metabolites was more than doubled by increasing the amount of pyridoxine (4.5 to 23 microM) in the incubation medium. Insulin (10 mU/ml), glucagon (1 nM), or epinephrine (10 microM) did not have any significant effect on the conversion of [14C]-pyridoxine to pyridoxal, pyridoxal phosphate, or pyridoxic acid. Our earlier observations of a large decrease in serum pyridoxal phosphate in the diabetic rat cannot be explained by any direct hormonal effects on pyridoxine metabolism.

Animals↗
PubMed1992

Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.

To determine the role of cytokines in mediating the decrease in ketones associated with infection, we studied the effect of endotoxin (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) on serum and hepatic ketone body levels (KB), serum free fatty acids (FFA), and hepatic malonyl-CoA levels. LPS decreased serum and hepatic KB in C57Bl/6 (LPS sensitive) mice, whereas it had little effect in C3H/HeJ (LPS resistant) mice, whose macrophages lack the ability to produce IL-1 and TNF in response to LPS, suggesting that IL-1 and TNF may mediate this effect. IL-1 and TNF decreased serum KB in both strains of mice. As seen with LPS, IL-1 decreased hepatic KB, whereas TNF had no such effect. LPS, IL-1, and TNF increased hepatic malonyl-CoA levels. TNF acutely raised serum FFA, whereas LPS and IL-1 did not. Postulating that the TNF-induced increase in FFA overrides the inhibitory effect of malonyl-CoA on fatty acid oxidation and ketogenesis, we used R-2-phenylisopropyladenosine to block TNF-induced lipolysis and demonstrated that in the absence of increased fatty acid flux, TNF inhibits KB formation. As seen with LPS, IL-1, but not TNF, decreased KB in the fasting state. These data suggest that IL-1 and TNF may mediate the antiketogenic effect of infection and that IL-1 has properties closest to that of LPS.

Animals↗
PubMed1992

In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.

The host response to infection and cancer produces disturbances in fatty acid (FA) oxidation and ketogenesis. Interferons (IFNs) stimulate lipolysis in cultured adipocytes. Since FA mobilization is a major stimulus for ketogenesis, we studied the effect of IFN alpha and IFN gamma on lipolysis and ketogenesis in intact mice. Both IFNs acutely stimulated lipolysis; however, their effects on ketogenesis differed. INF gamma increased serum and hepatic ketone body levels in parallel to its effect on serum FFA, whereas IFN alpha exerted a biphasic effect on ketogenesis. At low doses, IFN alpha increased serum and hepatic ketone body levels, whereas at higher doses, this ketogenic effect was abolished. To determine the mechanism of the biphasic response, we studied the effect of IFN alpha on hepatic malonyl-coenzyme-A (malonyl-CoA), the first committed intermediate in FA synthesis and an inhibitor of FA oxidation and ketogenesis. At low doses, IFN alpha had no effect on malonyl-CoA; however, higher doses of IFN alpha significantly increased malonyl-CoA levels, which could counterbalance its mobilization of FFA. In contrast, INF gamma had little effect on malonyl-CoA, and hence, the FA oxidation was not opposed. By using phenylisopropyladenosine to block IFN-induced lipolysis, we found that in the absence of increased FA flux, INF gamma did not exert a ketogenic effect. However, when IFN alpha-induced lipolysis was blocked, the higher doses of IFN alpha that raise malonyl-CoA levels were antiketogenic. These data suggest that both IFNs exert a ketogenic effect by stimulating lipolysis, but at higher doses the ketogenic effect of IFN alpha is counteracted by its effect on hepatic FA synthesis.

3-Hydroxybutyric Acid↗
PubMed1992

Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.

Hyperlipidemia frequently accompanies infectious diseases and may be due to increases in lipoprotein production or decreases in lipoprotein clearance. The administration of endotoxin (LPS) has been used to mimic infection and prior studies demonstrate that LPS produces hypertriglyceridemia. In the present study in rodents, the dose of LPS necessary to induce hyperlipidemia was orders of magnitude less than that necessary to induce shock and death. As little as 10 ng/100 g body weight induced hypertriglyceridemia and this increase in serum triglyceride levels occurred rapidly (78% increase at 2 h). At high doses of LPS (50 micrograms/100 g body weight), the clearance of triglyceride-rich lipoproteins was decreased. At low doses of LPS (100 ng/100 g body weight), triglyceride clearance was not altered but the hepatic secretion of triglyceride was increased. Low dose LPS stimulated hepatic de novo fatty acid synthesis and lipolysis, both of which provided a source of fatty acids for the increase in hepatic triglyceride production. High dose LPS did not increase hepatic fatty acid synthesis or peripheral lipolysis, and hepatic triglyceride secretion was not stimulated. Thus, low dose LPS produces hypertriglyceridemia by increasing hepatic lipoprotein production, while high dose LPS produces hypertriglyceridemia by decreasing lipoprotein catabolism. Administration of anti-tumor necrosis factor (TNF) antibodies or interleukin 1 (IL-1) receptor antagonist did not prevent the increase in serum triglyceride levels induced by LPS. However, anti-TNF antibodies and interleukin 1 receptor antagonist (IL-1ra) blocked the increase in serum triglycerides induced by TNF or IL-1, respectively. These data suggest that neither of these cytokines is absolutely required for the increase in serum triglycerides induced by LPS, raising the possibility that other cytokines, small molecular mediators, or LPS itself may play a crucial role.

Animals↗
PubMed1991

Amphibolic role of the Krebs cycle in the insulin-stimulated protein synthesis.

It has been a generally held view that insulin does not significantly affect the incorporation of amino acids into liver protein. This interpretation was based on data obtained from studies using the branched chain amino acids, which are poorly metabolized by the hepatic tissue. The effect of insulin on 14CO2 formation and protein incorporation of several 1-14C-labeled or U-14C-labeled amino acids was studied in isolated rat hepatocytes and diaphragm pieces. It was shown that insulin enhanced 14CO2 formation and protein incorporation primarily of those carbons of amino acids which are metabolized through the mitochondrial Krebs cycle. Using aminooxyacetic acid (0.5 mM), a potent inhibitor of the transamination reaction, it was shown that there exists an "insulin-sensitive" pool of glutamate which is preferentially utilized for protein synthesis in the presence of insulin. The insulin effect on protein incorporation of 14C-labeled glutamate generated in the Krebs cycle was abolished in the presence of aminooxyacetic acid. We interpret these results to signify that mitochondrial transamination of alpha-ketoglutarate to glutamate is essential for insulin stimulation of 14C incorporation into hepatocyte protein.

Alanine↗
PubMed1991

Differential effects of insulin, epinephrine, and glucagon on rat hepatocyte mitochondrial activity.

Oxidation of [2,3-14C]succinate carbons in the mitochondrial Krebs cycle was used as a probe to investigate the effects of insulin, epinephrine, glucagon, and 2,4-dinitrophenol (2,4-DNP) on isolated rat hepatocytes. Epinephrine, glucagon, and 2,4-DNP had a far greater stimulatory effect on 14CO2 formation from [2,3-14C]succinate than insulin. Unlike insulin, epinephrine and glucagon had no significant effect on the anabolic utilization of succinate carbons for protein synthesis. Our results suggest that although epinephrine, glucagon, and 2,4-DNP enhance the movement of tracer carbons through the Krebs cycle, only insulin is capable of enhancing amphibolite utilization for protein synthesis.

2,4-Dinitrophenol↗
PubMed1991

Extracellular phosphate requirement for insulin action on isolated rat hepatocytes.

Isolated rat hepatocytes were prepared in KHB buffer, pH 7.4; were centrifuged and washed twice in KHB buffer containing various amounts of phosphate and calcium; and were incubated at 30 degrees in the presence of tracer [2,3-14C]succinate and a 0.5 mM concentration of each of the 20 natural amino acids. Hepatocytes washed and incubated in KHB buffer containing less than 0.1 mM phosphate failed to show any insulin stimulation of [2,3-14C]succinate oxidation or protein incorporation of tracer carbons. The absence or presence of extracellular phosphate did not alter the specific activity of 32P-adenine nucleotides; they remained the same in the presence or absence of insulin. The maximal insulin stimulatory effect on succinate oxidation and tracer incorporation into protein was observed in the presence of 1.18 mM phosphate and 1.9 mM calcium ion. The lack of external phosphate did not prevent the stimulation of succinate oxidation by either glucagon on epinephrine, whereas removal of calcium from the medium abolished their hormonal effects. The lack of medium calcium also prevented the insulin stimulation of succinate oxidation and protein synthesis. Our data indicate that a diminished insulin responsiveness in hypophosphatemic patients may be due to the insensitivity of mitochondria to insulin in the hypophosphatemic state.

Animals↗